Diosmin is the International Nonproprietary Name assigned to the product 7-[[6-O-(6-Deoxy-α-L-mannopyranosyl)β-D-gluocopyranosyl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one (CAS 520-27-4), which has the following chemical structure:

Diosmin is a naturally occurring flavonoid glycoside that can be obtained from various plant sources.
Diosmin is used in therapy due to its pharmacological activity as phlebotonic and vascular protecting agent, so it is indicated, for example, for the treatment of chronic venous insufficiency.
Industrially, diosmin is usually manufactured starting from the flavonoid hesperidin, which is widely available by extraction from citrus fruits.
Structurally, diosmin only differs from hesperidin in the double bond between carbon atoms 2-3 of the benzopyran-4-one central ring, so hesperidin has the following chemical structure:

Therefore, for obtaining diosmin from hesperidin this single bond must be oxidized to a double bond.
In prior art, a number of processes have been disclosed to convert hesperidin into diosmin, that are suitable to be implemented industrially. Most of these processes are based on the use of halogens, namely iodine or bromine, for performing the oxidation step, typically using a halogenation/dehydrohalogenation mechanism to obtain the double bond.
Occasionally, the hydroxyl groups of hesperidin must be protected before performing the halogenation/dehydrohalogenation step.
One of the main difficulties faced in such processes is that special care has to be taken to eliminate iodinated or brominated intermediates or by-products formed during the process, so to obtain diosmin with an acceptable purity level as required, for example, in the European Pharmacopoeia, where the maximum allowed iodine content is 1000 ppm (0.1%).
In the processes disclosed so far, the elimination of iodine or bromine always requires basic conditions, either by treatment with hydroalcoholic alkaline solutions or, alternatively, with organic bases, such as morpholine or pyridine.
Thus, for example, in the German patent application DE2602314-A1 a process is disclosed for preparing diosmin wherein hesperidin is first acetylated using acetic anhydride, to protect the hydroxyl groups. The obtained acetylated hesperidin is isolated, and subsequently oxidized by treatment with bromine in a solvent such as ethyl acetate, ethylene chloride or acetic acid. The final dehydrobromination and deacetylation steps are performed in a hydroalcoholic alkaline solution, namely by treatment with a mixture of methanol and aqueous sodium hydroxide. The crude diosmin thus obtained is recrystallized, for example by dissolving it in a solution of sodium hydroxide in a mixture of water/methanol/pyridine, and subsequently acidifying with acetic acid to precipitate diosmin.
In the Spanish patent application ES440427 a process is disclosed wherein hesperidin is also first acetylated with acetic anhydride, using pyridine as catalyst, and subsequently it is brominated with N-bromosuccinimide in acetic acid and in the presence of bezoyl peroxide. The final dehydrobromination and deacetylation steps are also performed by treatment with a hydroalcoholic alkaline solution, using a mixture of ethanol and aqueous sodium hydroxide.
Alternatively, in the Italian patent IT1150612-B it is suggested the use of a phase transfer catalyst to achieve a complete dehydrobromination and deacetylation using milder conditions. Thus, according to this process, acetylated hesperidin is first brominated with bromine in 1,2-dichloroethane, and the following dehydrobromination and deacetylation step is performed in a biphasic system benzene/water or toluene/water using n-tetrabutylammonium sulfate as phase transfer catalyst.
Other processes disclosed in prior art, relate to the preparation of diosmin by halogenation/dehydrohalogenation of non-protected hesperidin, by performing the reaction in a weakly basic organic solvent, preferably pyridine, as described in the German patent DE2740950-A1.
Similarly, in the Belgian patent application BE904614-A1 it is disclosed that, as an alternative to the use of pyridine as solvent, hesperidin can be iodinated using an inert organic solvent, such as dimethylformamide or dimethylsulfoxide, but containing a certain amount of base to allow the elimination of iodine.
In the international patent application WO00/11009-A2 it is disclosed a process to obtain diosmin with low iodine content by reacting hesperidin with iodine in pyridine containing catalytic amounts of a mineral base, for example, sodium hydroxide, potassium hydroxide or calcium carbonate. The content of residual iodine can still be lowered by treatment of the final product with morpholine.
Therefore, despite the different alternatives proposed so far in the state of the art, the preparation of diosmin is still challenging, especially for obtaining it with low iodine and/or bromine content and using an economical and industrially-feasible process.
Particularly, in one way or another, all the proposed methods require the extensive use of different organic solvents, and thus, the obtained diosmin inevitably contains residual organic solvents, which is not desirable for its use as a drug. Moreover, the industrial use of organic solvents is always troublesome, since they involve high environmental impact and also potential occupational health hazards for the workers, apart from an increase in the manufacturing cost.
So, it would be desirable to develop an alternative method for manufacturing diosmin of high purity, especially with low iodine and/or bromine content, and avoiding the use of organic solvents.